In recent years, an ultrasonic diagnosis has been remarkably developed in a diagnosis of breast and abdomen portions because of such a feature that blood flow information can be acquired. In particular, an ultrasonic image pick-up technique using a contrast agent has been developed. Therefore, more accurate blood flow information has been acquired. In such an ultrasonic contrast, a micro bubble contrast agent including a large number of micro bubbles having a diameter of 1 to several μm, which are mixed into a liquid is mainly used with an injection in to a vein. The micro bubble is obtained by filling a gas (air or carbon fluoride) which is non-toxic to an organism in a shell comprising a substance (lecithin) which is non-toxic to the organism.
JP-A-9-164138 (Japanese Patent Laid-Open No. 164138/1997) has described an ultrasonic diagnosis image processing method of injecting a micro bubble ultrasonic contrast agent into a blood flow and sending an ultrasonic pulse to break the micro bubble in a tissue, thereby measuring, through an ultrasonic wave, the extent of the recirculation of the micro bubble in the tissue at a certain time interval after the breakdown of the micro bubble.
Also in an ultrasonic image pick-up technique, moreover, a Doppler signal and a harmonic signal have been increasingly utilized so that blood flow information in more tissues can be acquired. In particular, a blood flow movement can be evaluated more accurately by a combination with ultrasonic contrast.
JP-A-11-178824 has described a pulse inversion Doppler ultrasonic diagnosis image processing method comprising the steps of transmitting a modulated ultrasonic sequence into a body to make a phase difference on an ultrasonic echo obtained as a response thereof, receiving a set of ultrasonic echo signals responding to the transmitted sequence, and analyzing the set to separate phase shift information about linear and non-linear signal components.
In the detection of such a Doppler signal, however, a large signal sent from a tissue having a great movement such as a heart muscle or a harmonic signal generated from the tissue itself is mixed. Therefore, it is impossible to singly detect a micro bubble in a blood vessel.
There has been investigated so-called sub-harmonic imaging in which an ultrasonic wave having a plurality of continuous waves is irradiated to generate an image based on a sub-harmonic echo generated from only the micro bubble in the blood vessel. A sub-harmonic component is generated by only the chaotic oscillation and branch phenomenon of the micro bubble. Therefore, it has been supposed that the sub-harmonic imaging can acquire a higher contrast than that of harmonic imaging.
U.S. Pat. No. 5,706,819 has described an ultrasonic diagnosis image processing method of injecting a harmonic contrast agent into a subject and mutually inverting the polarity of a transmitted pulse to combine a received echo signal, thereby suppressing the harmonic component of a transmitted signal and removing a scattering to detect the influence of a harmonic contrast agent.
According to such a method, however, the sum of harmonics and sub-harmonics is detected. Therefore, the sub-harmonics cannot be detected singly.
Moreover, JP-A-2000-5167 has described an ultrasonic wave transmitting method of transmitting an ultrasonic wave including waves having an instantaneous sound pressure for breaking a micro balloon (a micro bubble) present respectively before and after at least one wave having an instantaneous sound pressure which does not break the micro balloon, in transmitting an ultrasonic wave having a plurality of continuous waves, and of reliably generating a sub-harmonic echo.
According to such a method, however, the micro balloon is broken. Therefore, it is impossible to continuously observe the micro balloon injected into a subject in a real time.
In recent years, furthermore, a mechanism for generating sub-harmonics has often been investigated. There has been known that ultrasonic waves having a plurality of continuous waves are irradiated to increase the intensity of sub-harmonics (Nico de Jong, First International Contrast Ultrasonic Wave Kyoto Symposium S1-1, Oct. 23, 1999).
In ultrasonic imaging, however, a space resolution is determined by the length of the transmitted continuous wave. Therefore, there is a problem in that the space resolution of an obtained ultrasonic image is reduced if an ultrasonic wave continuing for a long period is used.
As contrast agents for ultrasonic diagnosis, many ones are marketed or under clinical test. Examples thereof include Echovist®, Levovist® (Shering AG), Imagent® (Alliaancs Pharmaceutical Corp.), Optison™ (Molecular Biosystems, Inc.), EchoGen™ (SONUS Pharmaceutical, Inc.), Sonazoid™ (Nucomed Amersham plc), Definity™ (DuPont Pharmaceutical Co.), SonoVue ™ (Bracco Diagnostics Inc.), Quantison™ (Quadrant Healthcare plc), etc. These contrast agents are stabilized microbubbles of several μm in bubble size prepared by encapsulating the air or a gas of perfluorocarbon by a surfactant or a high molecular compound. These contrast agents have been developed mainly for keeping stability during storage as a chemical or in a blood liquid after injection, and techniques for enhancing strength of subharmonic are not employed therein.
In addition, with respect to the ultrasonic contrast agents, there have been disclosed a number of literature (for example, E. Leen, medicalmudi, 43(3), p. 17 (1999); Nico de Jong and Folkert J. Ten Cate, Ultrasonics, 34, p. 587 (1996); P. J. A. Frinking et al, J. Acoust. Soc., 105(3), p. 1989 (1999); P. A. Dayton et al, IEE Trans. Ultrason., 46(1), p. 220 (1999); and A. Bouakaz and K. K. Shung, 1999IEEE Ultrasonics Symposium, p. 1963) and patents (U.S. Pat. Nos. 5,855,865, 6,080,386, 5,948,387, International Patent Publication No. 505900/1998, International Patent Publication No. 501745/2000, International Patent Publication No. 502047/2000 and International Patent Publication No. 506122/2000). However, methods for strengthening subharmonic have not yet been found.
The mechanism how subharmonic echo is generated from the microbubbles has not fully been explained theoretically, though many studies have been started. In the recent studies, it is inferred that bubbles are chaotically oscillated by irradiated ultrasound (Nicchoi Kiso Gijutsu Kenkyukai Shiryo, vol. 100, No. 2, p. 29; P. M. Shankar et al, J. Acoust. Soc. Am., 106(4), 2014 (999); Zhen Ye, J. Acoust. Soc. Am., 100(4), 2011 (1996); Nico de Jong et al, 1st US Contrast abstracts, p. 29 (1999); etc.). Although analysis on oscillation of the microbubbles has proceeded in a dilute solution system, it has also been found that, in a high concentration region corresponding to the concentration of the actual ultrasonic contrast agent, there additionally appears a behavior as aggregates of micro bubbles (bubble clouds), thus extrapolation of the dilute solution system being meaningless (Nicchoi Kiso Gijutsu Kenkyukai Shiryo, vol. 100, No. 2, p. 1). That is, the subharmonic echo from the microbubbles is generated from the chaos of which the optimal region cannot theoretically be explained, and its behavior is more complicated due to formation of the bubble clouds, thus an ultrasonic scatterer capable of generating a strong subharmonic echo not being defined unequivocally.